The alcohol dehydrogenase 1C gene (ADH1C) gamma2gamma2 variant reportedly interacts with moderate alcohol consumption to increase HDL-cholesterol levels and reduce coronary heart disease (CHD). We undertook replication studies in two large population cohorts of women and men. 3234 women and 1313 men with relevant genotypic and phenotypic data from two prospective population cohorts were genotyped for ADH1C variants. No association was found between ADH1C variants and HDL-cholesterol, blood pressure or incident CHD, although ADH1C was associated with alcohol consumption. There was no evidence of interactions between ADH1C variants and moderate alcohol intake on HDL-cholesterol, blood pressure or CHD incidence. Life-long women abstainers had adverse risk factor profiles. Our findings do not support the hypothesis that ADH1C variants are associated with CHD risk in people who drink moderately.